1. Field of the Invention
The present invention relates to mitomycin N.sup.7 -alkyl phosphate derivatives, to their use as antitumor agents, and to pharmaceutical compositions containing them.
2. Background Art
Mitomycins and porfiromycin are a group of closely related antitumor antibiotics. Mitomycin C (Ia) is currently marketed in the United States under the tradename Mutamycin.RTM. for therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents. The structures of mitomycins C and A (Ib), porfiromycin (Ic), and N.sup.1a -methyl mitomycin A (Id) are shown below with the numbering for the ring portion of the molecules. Throughout the specification ##STR1## N.sup.7 - will refer to the nitrogen atom attached to the 7-position and N.sup.1a - to the aziridine nitrogen. The portion enclosed within the dashed lines is referred to in the art as mitosane.
A large number of mitomycin analogs have been prepared with the object of finding a compound with more favorable therapeutic properties, such as higher antitumor activity and/or less myelosuppressive than mitomycin C. Among literature references and patents on mitomycin derivatives, the following are considered to be relevant to the present invention.
Iyengar et al disclose compounds IIa-IIc in J. Med. Chem., 1981, 24: 974-981 and J. Med. Chem., 1983, 26: 16-20. ##STR2##
Kaneko et al in U.S. Pat. No. 4,642,352 disclose mitomycin derivatives having the formula III ##STR3## wherein R.sup.1 is selected from H, C.sub.1-6 alkyl, and R.sup.7, and R.sup.7 is inter alia (R.sup.b O).sub.2 P(X)-- and (R.sup.a).sub.2 P(X)-- wherein R.sup.a is for example, H, alkyl, cycloalkyl, aryl; and R.sup.b is for example, alkyl, aryl, aralkyl.
Compounds of the present invention are phosphate derivatives of compounds of formula II; they show good antitumor activity and lower toxicity relative to the parent hydroxy compound. The concept of phosphates as potential prodrugs is briefly discussed in the review article entitled "Rational for Design of Biologically Reversible Drug Derivatives: Prodrugs" (Sinkula and Yalkowsky, J. Pharm. Sci., 1975, 64: 181-210 at 189-191). Examples of phosphates of known antitumor agents include camptothecin (Japan Kokai 21-95,394 and 21-95,393, Derwent Abst. No. 87-281016 and 87-281015, respectively) and daunorubicin (U.S. Pat. No. 4,185,111).